Inhibiting endothelial cell function in normal and tumor angiogenesis using BMP type I receptor macrocyclic kinase inhibitors

Simple Summary Anti-angiogenesis agents have shown anti-cancer activity by preventing blood vessel ingrowth, thereby limiting tumour growth and metastasis. Although these molecules lead to prolonged overall survival of cancer patients, therapy resistance is easily acquired. Therefore, novel inhibitors against other signaling pathways mediating angiogenesis are needed to achieve more efficient and sustainable targeting of the angiogenesis process. Here, we synthesized and identified two compounds belonging to a new class of small molecules termed macrocyclics that selectively inhibit bone morphogenetic protein receptor kinase activity. One compound also inhibits vascular endothelial growth factor-induced signalling. Treatment studies using in vitro cultured cells and zebrafish embryos revealed that both compounds impaired endothelial cell function and decreased normal and tumour-induced angiogenesis. Both compounds might provide a steppingstone for the development of novel-angiogenesis therapeutic agents. Angiogenesis, i.e., the formation of new blood vessels from pre-existing endothelial cell (EC)-lined vessels, is critical for tissue development and also contributes to neovascularization-related diseases, such as cancer. Vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs) are among many secreted cytokines that regulate EC function. While several pharmacological anti-angiogenic agents have reached the clinic, further improvement is needed to increase clinical efficacy and to overcome acquired therapy resistance. More insights into the functional consequences of targeting specific pathways that modulate blood vessel formation may lead to new therapeutic approaches. Here, we synthesized and identified two macrocyclic small molecular compounds termed OD16 and OD29 that inhibit BMP type I receptor (BMPRI)-induced SMAD1/5 phosphorylation and downstream gene expression in ECs. Of note, OD16 and OD29 demonstrated higher specificity against BMPRI activin receptor-like kinase 1/2 (ALK1/2) than the commonly used small molecule BMPRI kinase inhibitor LDN-193189. OD29, but not OD16, also potently inhibited VEGF-induced extracellular regulated kinase MAP kinase phosphorylation in ECs. In vitro, OD16 and OD29 exerted strong inhibition of BMP9 and VEGF-induced ECs migration, invasion and cord formation. Using Tg (fli:EGFP) zebrafish embryos, we found that OD16 and OD29 potently antagonized dorsal longitudinal anastomotic vessel (DLAV), intra segmental vessel (ISV), and subintestinal vessel (SIV) formation during embryonic development. Moreover, the MDA-MB-231 breast cancer cell-induced tumor angiogenesis in zebrafish embryos was significantly decreased by OD16 and OD29. Both macrocyclic compounds might provide a steppingstone for the development of novel anti-angiogenesis therapeutic agents.Cancer Signaling networks and Molecular Therapeutic

Decreased motivation in the use of insecticide-treated nets in a malaria endemic area in Burkina Faso

<p>Abstract</p> <p>Background</p> <p>The use of insecticide-treated nets (ITN) is an important tool in the Roll Back Malaria (RBM) strategy. For ITNs to be effective they need to be used correctly. Previous studies have shown that many factors, such as wealth, access to health care, education, ethnicity and gender, determine the ownership and use of ITNs. Some studies showed that free distribution and public awareness campaigns increased the rate of use. However, there have been no evaluations of the short- and long-term impact of such motivation campaigns. A study carried out in a malaria endemic area in south-western Burkina Faso indicated that this increased use declined after several months. The reasons were a combination of the community representation of malaria, the perception of the effectiveness and usefulness of ITNs and also the manner in which households are organized by day and by night.</p> <p>Methods</p> <p>PermaNet 2.0^®and Olyset^®were distributed in 455 compounds at the beginning of the rainy season. The community was educated on the effectiveness of nets in reducing malaria and on how to use them. To assess motivation, qualitative tools were used: one hundred people were interviewed, two hundred houses were observed directly and two houses were monitored monthly throughout one year.</p> <p>Results</p> <p>The motivation for the use of bednets decreased after less than a year. Inhabitants' conception of malaria and the inconvenience of using bednets in small houses were the major reasons. Acceptance that ITNs were useful in reducing malaria was moderated by the fact that mosquitoes were considered to be only one of several factors which caused malaria. The appropriate and routine use of ITNs was adversely affected by the functional organization of the houses, which changed as between day and night. Bednets were not used when the perceived benefits of reduction in mosquito nuisance and of malaria were considered not to be worth the inconvenience of daily use.</p> <p>Conclusion</p> <p>In order to bridge the gap between possession and use of bednets, concerted efforts are required to change behaviour by providing accurate information, most particularly by convincing people that mosquitoes are the only source of malaria, whilst recognising that there are other diseases with similar symptoms, caused in other ways. The medical message must underline the seriousness of malaria and the presence of the malaria vector in the dry season as well as the wet, in order to encourage the use of bednets whenever transmission can occur. Communities would benefit from impregnated bednets and other vector control measures being better adapted to their homes, thus reducing the inconvenience of their use.</p